(S)-(+)-2-Amino-1-butanol; L-(+)-2-Amino-1-butanol; (S)-2-Amino-1-butanol -Drug Synthesis Database

【结构式】

【分子编号】48572

【品名】(S)-(+)-2-Amino-1-butanol; L-(+)-2-Amino-1-butanol; (S)-2-Amino-1-butanol

【CA登记号】5856-62-2

【分子式】C₄H₁₁NO

【分子量】89.13748

【元素组成】C 53.9% H 12.44% N 15.71% O 17.95%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：

2) The condensation of aldehyde (IV) with bromoform by means of LiOH in hot dioxane/water gives (±)-2-(benzo[b]thiophen-5-yl)-2-hydroxyacetic acid (XI), which is submitted to optical resolution by fractional crystallization of its 2(R)-aminobutanol salt in isopropanol and acidification with HCl to yield (R)-(-)-2-(benzo[b]thiophen-5-yl)-2-hydroxyacetic acid (XII). The cyclization of (XII) with acetone and concentrated H2SO4 affords (R)-(-)-5-(benzo[b]thiophen-5-yl)-2,2-dimethyl-1,3-dioxolan-4-one (XIII), which, by treatment with methanol and H2SO4, is converted into (R)-(-)-2-(benzo[b]thiophen-5-yl)-2-hydroxyacetic acid methyl ester (XIV). The protection of the OH group of (XIV) with dihydropyran (DHP) and pyridinium p-toluenesulfonate (Pyr·TsOH) affords the corresponding tetrahydropyranyl ether (XV), which is reduced with NaBH4 in ethanol, giving (R)-(-)-2-(benzo[b]thiophen-5-yl)-2-(tetrahydropyranyloxy)ethanol (XVI). Finally, this compound is condensed with 2-(diethylamino)ethyl chloride (XVII) by means of NaOH and tetrabutylammonium hydrogensulfate in toluene/water, followed by acidification with HCl. 3) The (R)-dioxolane (XIII) can also be obtained as follows: The racemic hydroxyacetic acid (XI) is cyclized with acetone and H2SO4 as before, giving the racemic dioxolane (XVIII). This compound is dissolved in hot (50 C) tert-amyl alcohol along with 1,8-diazabicyclo[5.4.0]-7-undecene (DCU); this solution is then seeded with a suspension of the (R)-(-)-isomer (XIII) in the same solvent and is slowly cooled at 25 C; a 81% yield of pure crystals of (R)-(-)-isomer (XIII) is obtained. This procedure allows for improving the yields by recovering the unused (S)-(+)-isomer.

参考文献中间体

合成目标

【1】 Martel, A.M.; Prous, J.; Castaner, J.; T-588. Drugs Fut 1997, 22, 4, 386.
【2】 Nakano, J.; Taya, N.; Chaki, H.; Yamafuji, T.; Momonoi, K. (Toyama Chemical Co., Ltd.); Benzo b thiophen-5-yl deriv. and process for producing the same. EP 0565965 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	48572	(S)-(+)-2-Amino-1-butanol; L-(+)-2-Amino-1-butanol; (S)-2-Amino-1-butanol	5856-62-2	C₄H₁₁NO	详情	详情
(IV)	16181	1-benzothiophene-5-carbaldehyde		C₉H₆OS	详情	详情
(XI)	16188	2-(1-benzothiophen-5-yl)-2-hydroxyacetic acid		C₁₀H₈O₃S	详情	详情
(XII)	16189	(2R)-2-(1-benzothiophen-5-yl)-2-hydroxyethanoic acid		C₁₀H₈O₃S	详情	详情
(XIII)	16190	(5R)-5-(1-benzothiophen-5-yl)-2,2-dimethyl-1,3-dioxolan-4-one		C₁₃H₁₂O₃S	详情	详情
(XIV)	16191	methyl (2R)-2-(1-benzothiophen-5-yl)-2-hydroxyethanoate		C₁₁H₁₀O₃S	详情	详情
(XV)	16192	methyl (2S)-2-(1-benzothiophen-5-yl)-3-(tetrahydro-2H-pyran-2-yloxy)propanoate		C₁₇H₂₀O₄S	详情	详情
(XVI)	16193	(2R)-2-(1-benzothiophen-5-yl)-3-(tetrahydro-2H-pyran-2-yloxy)-1-propanol		C₁₆H₂₀O₃S	详情	详情
(XVII)	16194	2-chloro-N,N-diethyl-1-ethanamine; N-(2-chloroethyl)-N,N-diethylamine	100-35-6	C₆H₁₄ClN	详情	详情
(XVIII)	16195	5-(1-benzothiophen-5-yl)-2,2-dimethyl-1,3-dioxolan-4-one		C₁₃H₁₂O₃S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

An efficient synthesis of AMP-579 has been reported: Reaction of the chiral amine (I) with tosyl chloride and NaOH in methyl tert-butyl ether (MTBE) gives the tosyl aziridine (II), which is condensed with 3-chlorothiophene (III) by means of n-BuLi to yield the tosyl amide (IV). Condensation of amide (IV) with 2,4-difluoro-3-nitropyridine (V) obtained by reaction of 2,4-dichloro-3-nitropyridine (VI) with KF and 18-crown-6 (18-C-6) in hot 1-methyl-2-pyrrolidinone (NMP) by means of t-BuOK in THF affords the disubstituted tosyl amide (VII). Condensation of compound (VII) with the cyclopentanecarboxamide (VIII) by means of K2CO3 in NMP provides the corresponding adduct (IX), which is hydrogenated with H2 over Pt in methanol/ethyl acetate to give the aminopyridine (X). Cyclization of (X) with HC(OEt)3 by means of hot Ac2O yields the imidazopyridine (XI), which is detosylated with Mg in MeOH or LiEt3BH in THF to afford the protected deazapurine (XII). Finally, the acetonide group of (XII) is eliminated by treatment with concentrated HCl in THF.

参考文献中间体

合成目标

【1】 O'Brien, M.K.; Powner, T.H.; Truesdale, L.K.; Kubiak, G.G.; Sledeski, A.W.; Powers, M.R.; Efficient synthesis of AMP579, a novel adenosine A1/A2 receptor agonist. J Org Chem 2000, 65, 23, 8114.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	48572	(S)-(+)-2-Amino-1-butanol; L-(+)-2-Amino-1-butanol; (S)-2-Amino-1-butanol	5856-62-2	C₄H₁₁NO	详情	详情
(II)	48573	(2R)-2-ethyl-1-[(4-methylphenyl)sulfonyl]aziridine		C₁₁H₁₅NO₂S	详情	详情
(III)	48574	3-Chlorothiophene; 3-Thienyl chloride	17249-80-8	C₄H₃ClS	详情	详情
(IV)	48575	N-[(1R)-1-[(3-chloro-2-thienyl)methyl]propyl]-4-methylbenzenesulfonamide		C₁₅H₁₈ClNO₂S₂	详情	详情
(V)	48576	2,4-difluoro-3-nitropyridine		C₅H₂F₂N₂O₂	详情	详情
(VI)	23847	2,4-dichloro-3-nitropyridine		C₅H₂Cl₂N₂O₂	详情	详情
(VII)	48577	N-[(1R)-1-[(3-chloro-2-thienyl)methyl]propyl]-N-(2-fluoro-3-nitro-4-pyridinyl)-4-methylbenzenesulfonamide		C₂₀H₁₉ClFN₃O₄S₂	详情	详情
(VIII)	48578	(3aS,4R,6S,6aR)-6-[(ethylamino)carbonyl]-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-aminium benzoate		C₁₈H₂₆N₂O₅	详情	详情
(IX)	48579	(3aR,4S,6R,6aS)-6-[(4-[[(1R)-1-[(3-chloro-2-thienyl)methyl]propyl][(4-methylphenyl)sulfonyl]amino]-3-nitro-2-pyridinyl)amino]-N-ethyl-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxole-4-carboxamide		C₃₁H₃₈ClN₅O₇S₂	详情	详情
(X)	48580	(3aR,4S,6R,6aS)-6-[(3-amino-4-[[(1R)-1-[(3-chloro-2-thienyl)methyl]propyl][(4-methylphenyl)sulfonyl]amino]-2-pyridinyl)amino]-N-ethyl-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxole-4-carboxamide		C₃₁H₄₀ClN₅O₅S₂	详情	详情
(XI)	48581	(3aR,4S,6R,6aS)-6-(7-[[(1R)-1-[(3-chloro-2-thienyl)methyl]propyl][(4-methylphenyl)sulfonyl]amino]-3H-imidazo[4,5-b]pyridin-3-yl)-N-ethyl-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxole-4-carboxamide		C₃₂H₃₈ClN₅O₅S₂	详情	详情
(XII)	48582	(3aR,4S,6R,6aS)-6-[7-([(1R)-1-[(3-chloro-2-thienyl)methyl]propyl]amino)-3H-imidazo[4,5-b]pyridin-3-yl]-N-ethyl-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxole-4-carboxamide		C₂₅H₃₂ClN₅O₃S	详情	详情

合成路线3

该中间体在本合成路线中的序号：(VI)

Condensation of 2,6-dichloropurine (I) with benzylamine (II) in boiling butanol afforded 6-(benzylamino)-2-chloropurine (III), which was subsequently alkylated at the 9-N with isopropyl bromide (IV), yielding purine (V). The 2-chloro group was finally displaced with (R)-2-amino-1-butanol (VI) in a sealed tube at 160 C to provide the title compound.

参考文献中间体

合成目标

【1】 Wang, S.; et al.; Synthesis and configuration of the cyclin-dependent kinase inhibitor roscovitine and its enantiomer. Tetrahedron Asymmetry 2001, 12, 20, 2891.
【2】 Havlicek, L.; et al.; Cytokinin-derived cyclin-dependent kinase inhibitors: Synthesis and cdc2 inhibitory activity of olomoucine and related compounds. J Med Chem 1997, 40, 4, 408.
【3】 Meijer, L.; Bisagni, E.; Legraverend, M. (CNRS (Centre National de la Recherche Scientifique)); Novel purine derivs. having, in particular, antiproliferative properties, and biological uses thereof. EP 0874847; FR 2741881; JP 2000501408; US 2002049218; US 6316456; WO 9720842 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	25254	2,6-dichloro-9H-purine	5451-40-1	C₅H₂Cl₂N₄	详情	详情
(II)	15147	Benzylamine; Phenylmethanamine	100-46-9	C₇H₉N	详情	详情
(III)	36315	N-benzyl-2-chloro-9H-purin-6-amine; N-benzyl-N-(2-chloro-9H-purin-6-yl)amine		C₁₂H₁₀ClN₅	详情	详情
(IV)	32658	2-bromopropane	75-26-3	C₃H₇Br	详情	详情
(V)	36316	N-benzyl-2-chloro-9-isopropyl-9H-purin-6-amine; N-benzyl-N-(2-chloro-9-isopropyl-9H-purin-6-yl)amine		C₁₅H₁₆ClN₅	详情	详情
(VI)	48572	(S)-(+)-2-Amino-1-butanol; L-(+)-2-Amino-1-butanol; (S)-2-Amino-1-butanol	5856-62-2	C₄H₁₁NO	详情	详情

Extended Information